Research Projects

Male infertility is a global health issue, with sperm counts dropping at a higher annual rate due to environmental chemicals affecting endocrine signaling. Estrogen Related Receptors (ERRs), which are phylogenetic peers of steroid receptors, are potential candidates for investigating male reproductive health. Mammals, including humans, have three ERR isoforms, but their function in male fertility is unknown. Studies in Drosophila melanogaster revealed that deficiency of the ERR homologue (dERR) reduced male fertility due to its role in testicular morphogenesis, spermatogenesis, energy metabolism, and sperm motility. This project proposes to identify human ERRs (hERRs) functional in male fertility and translate this knowledge into toxicology screening platforms. The project will follow the classical genetic route of heterologous expression of hERR isoforms in Drosophila melanogaster males, using CRISPR-Cas9 tools to generate testes/germ-line specific dERR knockout males. Transgenic flies with cDNAs of hERRα, hERRβ, or hERRγ will be generated through cloning and germ-line transformation of Drosophila embryos. To identify hERRs essential for male fertility, Drosophila males who over-express hERR isoforms in the absence of dERR through genetic crosses will be generated. A gene-switch model based on the identified hERR will be developed using molecular tools in Drosophila. This project has both fundamental and translational significance, as it will be the first to identify hERR isoforms involved in male fertility and provide insights into their relevance to testicular development, spermatogenesis, and sperm motility. Additionally, hERR-based gene-switch flies will provide a throughput xenobiotic screening platform to evaluate potential endocrine disruptors and their ability to hamper ERR activity and human male fertility.